Phenazepam

Phenazepam is the first benzodiazepine tranquilizer created in the USSR .

In the early 1970s, a group of scientists under the leadership of V. V. Zakusova received a state order for the creation of a domestic tranquilizer. The molecule was synthesized at the Odessa Institute of Physics and Chemistry of the Academy of Sciences of the Ukrainian SSR (S. A. Andronati and A. V. Bogatsky ) ^[3] . The development of phenazepam is associated with the names of many other major scientists — S. B. Seredenina and T. A. Voronina (pharmacological screening, selection and study), G. Ya. Avrutsky and Yu. A. Aleksandrovsky (clinical efficacy and safety).

For his receipt (1974), introduction (1978) and the creation of a scientific basis for a new branch of military medicine ( military psychopharmacology ) to a group of Soviet scientists - G. Ya. Avrutsky, Yu. A. Alexandrovsky, S. A. Andronati, A. V. Bogatsky , Yu. I. Vikhlyaevu, T. A. Voronina, V. V. Zakusov, A. L. Zyubanu, B. V. Ovchinnikov, S. B. Seredeninu, L. I. Spivak, G. V. Chuchkin - Awarded State Prize of the USSR (1980). ^{[4] [5]}

Synthesis scheme according to the method of S. A. Andronati, A. V. Bogatsky and Yu. I. Vikhlyaev, developed at the Physicochemical Institute of the Academy of Sciences of the Ukrainian SSR ^[3] :

First, 2- (o-chlorobenzoylamino) -5-bromo-2-chlorobenzophenone is obtained by acylation of p-bromoaniline with o-chlorobenzoic acid chloride in the presence of a catalyst - zinc chloride . 2- (o-chlorobenzoylamino) -5-bromo-2-chlorobenzophenone is hydrolyzed with aqueous sulfuric acid to give 2-amino-5-bromo-2-chlorobenzophone. 2-amino-5-bromo-2-chlorobenzofon is acylated with chloroamide hydrochloride of aminoacetic acid hydrochloride . Then 2- (aminomethylbronylamino) -5-bromo-2-chlorobenzophenone hydrochloride is formed, which is transferred to the base with aqueous ammonia , and then thermally cycled to bromohydrochlorophenylbenzodiazepine ^[2] .

Amino-acetic acid chloride hydrochloride is obtained by treating amino-acetic acid with phosphorus (V) chloride in chloroform .

Phenazepam is a highly active tranquilizer . It is superior to other benzodiazepine and abenzodiazepine tranquilizers by virtue of tranquilizing and anxiolytic (anti-anxiety) effects ^[6] ; also has a pronounced anticonvulsant, muscle relaxant (muscle-relaxing) and hypnotic effects. Surpasses diazepam in anti-anxiety and hypnotic effects ^[7] . The strength of the hypnotic effect is close to nitrazepam ^[1] . When used together with sleeping pills and opioid drugs, there is a mutual reinforcement of the depressant effect on the central nervous system .

At the stage of preclinical research in animal experiments, N. Ya. Golovenko and employees of the Odessa I. Mechnikov State University studied the parameters of ADME (absorption, distribution, metabolism and excretion) of the active pharmaceutical ingredient phenazepam. The results were included in the dossier of the drug submitted to the Regulatory Authority. The peak concentration of the drug in the blood plasma is reached within 1-2 hours after oral administration. The half-life is from 6 to 18 hours.

Phenazepam is prescribed:

• with various neurotic , neurosis-like, psychopathic and psychopathic states, accompanied by anxiety, fear, increased irritability, emotional lability ^[1] .
• with obsession , phobias , hypochondria syndromes, including hypochondria- senesthopathic (including those resistant to the action of other tranquilizers); with phobias and obsessions, they are especially effective in combination with perphenazine (etaderazine) and trifluoperazine (triftazine) ^[8] ,
• with psychogenic psychoses , panic reactions, etc., as it removes the state of anxiety and fear ^[1] ,
• for stopping (relieving) alcohol withdrawal ^[1] and delirium tremens (a condition resulting from a sudden cessation of alcohol intake occurring at the second to third stages of alcoholism ) ^[9]
• as an anticonvulsant (mainly for local, small, abortive seizures) ^[8] , also for the treatment of patients with temporal epilepsy and myoclonic epilepsy ^[10] ,
• as a sleeping pill
• for sedation in preparation for surgery ^[11] ,
• for the prevention of emotional stress and fear states ^[10] ,
• for the treatment of hyperkinesis and nerve tics ^[10] ,
• with muscle rigidity ^[10] ,
• with vegetative dysfunctions and vegetative lability ^[10] .
• reduces affective tension in delusional disorders .

In combinations:

• with severe psychomotor agitation in manic or psychotic patients (in combination with neuroleptics and lithium salts ) ^[12] .

Increases the inhibitory effect of gamma-aminobutyric acid (GABA) on the transmission of nerve impulses ^[13] . Stimulates DB receptors (in the allosteric center, etc.) ^[13] .

Inhibits polysynaptic spinal reflexes, reduces the excitability of the subcortical structures of the brain ( thalamus , hypothalamus and limbic system ) ^[13] .

The anti-anxiety effect is due to the effect on the almond - shaped complex of the limbic system ^[13] . This effect reduces anxiety, fear, anxiety and emotional stress.

Sedation is associated with the effect on the nonspecific nuclei of the thalamus and the reticular formation of the brain stem ^[13] . In particular, this effect also reduces the symptoms of neurotic origin , fear and anxiety ^[13] .

The hypnotic effect is associated with inhibition of the cells of the reticular formation of the brain stem. Phenazepam reduces the effects of vegetative, emotional , motor (motor) stimuli that can disrupt the mechanism of falling asleep, and helps to fall asleep faster.

Anticonvulsant action occurs due to increased presynaptic inhibition. The excited state of the focus (excited nervous structure or group of neurons) does not eliminate, but the spread of convulsive impulse is suppressed.

The central muscle relaxant effect arises due to the inhibition of both monosynaptic (to a small extent) and polysynaptic spinal afferent inhibitory pathways. Probably, direct inhibition of the function of muscles and motor nerves is also caused.

Hypersensitivity (including to other benzodiazepines), coma , shock , myasthenia gravis , angle-closure glaucoma (acute onset or predisposition), acute alcohol poisoning (with the weakening of vital functions), narcotic analgesics and sleeping medications, severe chronic obstructive pulmonary disease (possibly increased respiratory failure), acute respiratory failure, severe depression (suicidal tendencies may occur) ; pregnancy (especially the first trimester), lactation period, age up to 18 years (safety and efficacy not determined).

With caution. Hepatic and / or renal failure, cerebral and spinal ataxia, drug dependence in history, susceptibility to substance abuse , hyperkinesis, organic brain diseases, psychosis (paradoxical reactions are possible), hypoproteinemia, sleep apnea (established or suspected), elderly age.

From the central nervous system and peripheral nervous system: at the beginning of treatment (especially in elderly patients) - drowsiness, fatigue, dizziness, decreased ability to concentrate, ataxia , disorientation, instability of gait, slowing down of mental and motor responses, confusion; rarely - headache, euphoria , depression , tremor , memory loss, impaired motor coordination (especially at high doses), depressed mood, dystonic extrapyramidal reactions (uncontrolled movements, including the eyes), asthenia , myasthenia gravis , dysarthria , epileptic seizures (in patients with epilepsy); extremely rarely - paradoxical reactions (aggressive outbursts, psychomotor agitation , fear, suicidal tendency, muscle spasm, hallucinations , agitation, irritability, anxiety, insomnia).

On the part of the blood-forming organs: leukopenia , neutropenia , agranulocytosis (chills, hyperthermia , sore throat, excessive fatigue or weakness), anemia , thrombocytopenia .

On the part of the digestive system: dry mouth or drooling, heartburn , nausea, vomiting, loss of appetite, constipation or diarrhea ; abnormal liver function, increased activity of liver transaminases and alkaline phosphatase , jaundice .
On the part of the urogenital system: urinary incontinence, urinary retention, impaired renal function, decreased or increased libido , dysmenorrhea , priapism.

Allergic reactions: skin rash, itching.

Influence on the fetus: teratogenicity (especially I trimester), central nervous system depression, respiratory failure and suppression of sucking reflex in newborns whose mothers used the drug.
Local reactions: phlebitis or venous thrombosis (redness, swelling or pain at the injection site).

Other: addiction, drug addiction; decrease in blood pressure; rarely - visual impairment ( diplopia ), weight loss, tachycardia .

With a sharp decrease in dose or discontinuation of treatment, “withdrawal” syndrome (irritability, nervousness, sleep disorders, dysphoria, smooth muscle spasm of the internal organs and skeletal muscles, depersonalization , increased sweating, depression, nausea, vomiting, tremor, and perception disorders, including hyperacusia , paresthesia , photophobia , tachycardia, convulsions, rarely - acute psychosis).

Side Effect Correction

Mesocarb (sydnocarb), as well as the specific antagonist of benzodiazepine receptors, flumazenil , is effective as a corrector that reduces or removes the side effects of phenazepam ^[1] .

Symptoms: severe drowsiness, prolonged confusion, decreased reflexes, prolonged dysarthria, nystagmus, tremor, bradycardia, shortness of breath or difficulty breathing, decreased blood pressure, coma.

Treatment: gastric lavage, taking activated charcoal. Symptomatic therapy (maintaining breathing and blood pressure), the introduction of flumazenil (in the hospital). Hemodialysis is ineffective.

Assign phenazepam inside in pill form. On an outpatient basis, adults are prescribed 0.00025–0.0005 g (0.25–0.5 mg) 2-3 times a day ^[1] . In the hospital, the daily dose may be increased to 0.003-0.005 g (3-5 mg) ^[1] ; in the treatment of epilepsy, the daily dose ranges from 0.002 to 0.01 g (2-10 mg) ^[1] .

To stop alcohol withdrawal, 0.0025-0.005 g (2.5-5 mg) per day is prescribed ^[1] . For sleep disorders, they take 0.00025–0.001 g (0.25–1 mg) 20–30 minutes before sleep ^[1] . Sometimes the dose is increased to 0.0025 g (2.5 mg) ^[1] . The maximum daily dose should not exceed 0.01 g ^[1] .

When treating depersonalization, phenazepam is prescribed in large (4–8 mg) and very large (up to 20 mg) daily doses, which is explained by the fact that patients with depersonalization are resistant not only to the therapeutic effect of benzodiazepines, but also to their side effects ^[14]

For the treatment of mild anxiety with long-term therapy — 0.5–3 mg per day, with severe anxiety (maximum doses), 3–10 mg ^[12] .

Inhibition of cardiac, respiratory activity, as well as depression of consciousness, uncontrolled movements, pronounced confusion are noted.

Enhances the effects of alcohol , antipsychotics , antidepressants , analgesics , sleeping pills ^[1] and sedatives ^[15] . Especially dangerous is the combination of phenazepam with alcohol. Tranquilizers in combination with alcohol can cause pathological intoxication , respiratory depression, coma , respiratory depression, death ^[16] . Phenazepam should not be combined with barbiturates and MAO inhibitors . The combined use of phenazepam and MAO inhibitors can lead to toxic effects on the central nervous system ^[15] .

Phenazepam should be stored in a dry, cool, dark place.

By country

In Russia, phenazepam is permitted and is not included in the list of psychotropic substances restricted to distribution (unlike some other benzodiazepines on Schedule III: alprazolam , diazepam , clonazepam , lorazepam ).

Tatyana Klimenko, a narcologist and director of the branch of the Serbsky National Medical Research Center of Psychiatry and Narcology, believes that phenazepam is not subject to quantitative accounting, since the manufacturing company Valenta Farm has influenced the authorities and thus achieves an increase in drug sales ^[17] .

In Ukraine, in accordance with Resolution No. 770 of the Cabinet of Ministers of Ukraine dated May 6, 2000, phenazepam belongs to List II of the list of narcotic drugs, psychotropic substances and precursors, the circulation of which is limited in Ukraine and for which certain control measures are excluded ^[18] .

In the US, phenazepam is not approved by the Food and Drug Administration , therefore it is banned for sale as a medicine, but it is also not included in the list of controlled substances ^[19] .

In Germany, phenazepam is in Schedule III ( Ger . Anlage III ), and it is illegal to sell and store this drug without a prescription ^[20] . The drug may be prescribed by doctors, but requires a special prescription form.

UN and WHO Decisions

On March 18, 2016, the UN Commission on Narcotic Drugs was included in the list of substances subject to special control ^[21] . A WHO committee recommended the addition of phenazepam to the Schedule IV Convention on Psychotropic Substances of 1971 ^[22] .

Importation into the customs territory

Phenazepam is listed in the annex to the Decision of the Board of the Eurasian Economic Commission "On measures of non-tariff regulation" in the list of the section "Narcotic drugs, psychotropic substances and their precursors" in the list of goods for which a permit is established for importation into the customs territory of the Eurasian Economic Union and / or export from the customs territory of the Eurasian Economic Union ^[23] . This means that the drug must be subject to customs declaration, non-declaration of phenazepam at customs is an administrative offense under Article 16.2 of Part 1 of the Administrative Code of the Russian Federation.

• Samsonova, Tamara Mitrofanovna

• Instructions for medical use of the drug Fenazepam® (rus.) . State register of medicines . Ministry of Health of the Russian Federation (October 19, 2018). The appeal date is June 16, 2019.
• Pharmacopoeial article FS 42-0285-07 . - Ministry of Health of the Russian Federation, 2007.
• Phenazepam® (Phenazepamum) . [Instructions for use and formula] (rus.) . Encyclopedia of drugs and pharmacy assortment RLS® (September 12, 2018) .
• Bromohydrochlorophenylbenzodiazepine (Bromdihydrochlorphenylbenzodiazepine) . [Description of the active substance] (rus.) . Encyclopedia of drugs and pharmacy assortment RLS® .